EP4 agonists as agents for lowering intraocular pressure

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound which is a EP 4  agonist.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is a continuation of 10/346,828, filedJan. 16, 2003, which is a continuation in part of Ser. No. 09/882,720,filed Jun. 14, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to EP₄ agonists, for example 3, 7or 3 and 7 thia or oxa prostanoic acid derivatives as potent ocularhypotensives that are particularly suited for the management ofglaucoma.

[0003] 1. Background of the Invention

[0004] 2. Description of Related Art

[0005] Ocular hypotensive agents are useful in the treatment of a numberof various ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

[0006] Glaucoma is a disease of the eye characterized by increasedintraocular pressure. On the basis of its etiology, glaucoma has beenclassified as primary or secondary. For example, primary glaucoma inadults (congenital glaucoma) may be either open-angle or acute orchronic angle-closure. Secondary glaucoma results from pre-existingocular diseases such as uveitis, intraocular tumor or an enlargedcataract.

[0007] The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

[0008] Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

[0009] Considering all types together, glaucoma occurs in about 2% ofall persons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

[0010] Certain eicosanoids and their derivatives have been reported topossess ocular hypotensive activity, and have been recommended for usein glaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

[0011] Various types of prostaglandins are known, depending on thestructure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chain indicated by numerical subscriptsafter the generic type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β e.g. prostaglandinF_(2α)(PGF_(2β))].

[0012] Prostaglandins were earlier regarded as potent ocularhypertensives, however, evidence accumulated in the last decade showsthat some prostaglandins are highly effective ocular hypotensive agents,and are ideally suited for the long-term medical management of glaucoma(see, for example, Bito, L. Z. Biological Protection withProstaglandins, Cohen, M. M., ed., Boca Raton, Fla, CRC Press Inc.,1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the MedicalTreatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,Grune & Stratton, 1984, pp. 477505. Such prostaglandins include PGF_(2α)PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

[0013] Although the precise mechanism is not yet known experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

[0014] The isopropyl ester of PGF_(2β) has been shown to havesignificantly greater hypotensive potency than the parent compound,presumably as a result of its more effective penetration through thecornea. In 1987, this compound was described as “the most potent ocularhypotensive agent ever reported” [see, for example, Bito, L. Z., Arch.Ophthalmol. 105, 1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

[0015] Whereas prostaglandins appear to be devoid of significantintraocular side effects, ocular surface (conjunctival) hyperemia andforeign-body sensation have been consistently associated with thetopical ocular use of such compounds, in particular PGF_(2α) and itsprodrugs, e.g., its 1-isopropyl ester, in humans. The clinicalpotentials of prostaglandins in the management of conditions associatedwith increased ocular pressure, e.g. glaucoma are greatly limited bythese side effects.

[0016] In a series of co-pending United States patent applicationsassigned to Allergan, Inc. prostaglandin esters with increased ocularhypotensive activity accompanied with no or substantially reducedside-effects are disclosed. The co-pending USSN 596,430 (filed Oct. 10,1990, now U.S. Pat. No. 5,446,041), relates to certain11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl,11-valeryl, and 11-isovaleryl PGF_(2α). Intraocular pressure reducing15-acyl prostaglandins are disclosed in the co-pending application USSN175,476 (filed Dec. 29, 1993). Similarly, 11,15-9,15 and 9,11-diestersof prostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known tohave ocular hypotensive activity. See the co-pending patent applicationsUSSN Nos. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274),584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) and 585,284(filed Sep. 18, 1990, now U.S. Pat. No. 5,034,413). The disclosures ofall of these patent applications are hereby expressly incorporated byreference.

SUMMARY OF THE INVENTION

[0017] The present invention concerns a method of treating ocularhypertension which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of an EP₄ agonist, e.g.a compound of formula I

[0018] wherein hatched lines represent the a configuration, a trianglerepresents the β configuration, a wavy line represents either the αconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond;

[0019] A and B are independently selected from the group consisting ofO, S and CH₂; provided that at least one of A or B is S;

[0020] D represents a covalent bond or CH₂, O, S or NH;

[0021] X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR² or

[0022] Y is O, OH, OCOR², halogen or cyano;

[0023] Z is CH₂ or a covalent bond;

[0024] R is H or R²;

[0025] R is H, R²,phenyl, or COR²;

[0026] R² is C₁-C₅ lower alkyl or alkenyl;

[0027] R³ is benzothienyl, benzofuranyl, naphthyl, or substitutedderivatives thereof, wherein the substituents maybe selected from thegroup consisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, NR², CO₂R andOR; and

[0028] R⁴ is hydrogen or C₁-C₅ alkyl.

[0029] In a still further aspect, the present invention relates to apharmaceutical product, comprising

[0030] a container adapted to dispense its contents in a metered form;and

[0031] an ophthalmic solution therein, as hereinabove defined.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0032]FIG. 1 is a schematic of the chemical synthesis of a certainintermediate for the compounds of the invention as disclosed in Examples1 through 3.

[0033]FIG. 2 is a schematic of the chemical synthesis of certaincompounds related to the compounds of the invention as disclosed inExamples 4 through 7.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to the use of EP₄ agonists, e.g. 3,7 and 3 and 7 thia or oxa prostanoic acid derivatives, as ocularhypotensives. The compounds used in accordance with the presentinvention are encompassed by the following structural formula I:

[0035] A preferred group of the compounds of the present inventionincludes compounds that have the following structural formula II:

[0036] Another preferred group includes compounds having the formulaIII:

[0037] In the above formulae, the substituents and symbols are ashereinabove defined.

[0038] In the above formulae:

[0039] Preferably A and B are both S.

[0040] Preferably D represents a covalent bond or is CH₂; morepreferably D is CH₂.

[0041] Preferably Z represents a covalent bond.

[0042] Preferably R is H.

[0043] Preferably R¹ is H.

[0044] Preferably R⁴ is hydrogen or methyl, most preferably hydrogen.

[0045] Preferably Y=O.

[0046] Preferably X is CO₂R and more preferably R is selected from thegroup consisting of H, methyl, i-propyl and n-propenyl.

[0047] The above compounds of the present invention may be prepared bymethods that are known in the art or according to the working examplesbelow. The compounds, below, are especially preferred representative, ofthe compounds of the present invention.

[0048]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0049]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0050]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester,

[0051]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0052]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-O-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0053]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester,

[0054]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0055]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocydopentylsulfanyl]propylsulfanyl}aceticacid,

[0056]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester,

[0057]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0058]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0059]{3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0060]{3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0061]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0062]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,

[0063]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0064]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(naphthyl)but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,

[0065]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester and

[0066]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester.

[0067] Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

[0068] For ophthalmic application, preferably solutions are preparedusing a physiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

[0069] Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

[0070] Tonicity adjustors may be added as needed or convenient. Theyinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

[0071] Various buffers and means for adjusting pH may be used so long asthe resulting preparation is ophthalmically acceptable. Accordingly,buffers include acetate buffers, citrate buffers, phosphate buffers andborate buffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

[0072] In a similar vein, an ophthalmically acceptable antioxidant foruse in the present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

[0073] Other excipient components which may be included in theophthalmic preparations are chelating agents. The preferred chelatingagent is edentate disodium, although other chelating agents may also beused in place or in conjunction with it.

[0074] The ingredients are usually used in the following amounts:Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle  0-40 tonicity adjustor  1-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

[0075] The actual dose of the active compounds of the present inventiondepends on the specific compound, and on the condition to be treated;the selection of the appropriate dose is well within the knowledge ofthe skilled artisan.

[0076] The ophthalmic formulations of the present invention areconveniently packaged in forms suitable for metered application, such asin containers equipped with a dropper, to facilitate the application tothe eye. Containers suitable for dropwise application are usually madeof suitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

[0077] The invention is further illustrated by the followingnon-limiting Examples, which are summarized in the reaction schemes ofFIGS. 1 and 2 wherein the compounds are identified by the samedesignator in both the Examples and the Figures.

Example 1

[0078] (R)-4-(tert-Butyldimethylsilanyloxy)cyclopent-2-enone (2).

[0079] Tetrapropylammonium perruthenate (9.4 mg, 0.027 mmol) was addedto a mixture of (1S,4R)-4-(tert-butyldimethylsilanyloxy)cyclopent-2-enol prepared, accordingto Tetrahedron Letters, Vol. 37, No. 18, 1996, pp. 3083-6, (118.6 mg,0.54 mmol), 4-methylmorpholine N-oxide (94.9 mg, 0.81 mmol) and crushed4Å sieves (270 mg) in CH₂Cl₂ (10 mL). The mixture was stirred for 30 minand was passed through a plug of silica gel with CH₂Cl₂. The filtratewas concentrated in vacuo to give 100 mg (86%) of the above titledcompound.

Example 2

[0080](R)-4-(tert-Butyldimethylsilanyloxy)-6-oxabicyclo[3.1.0]hexan-2-one (3).

[0081] Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% wt. % solution inwater) and 1N NaOH (46 μL, 0.046 mmol) were added to a solution of enone2 (2.5 g, 11.5 mmol) in MeOH (30 mL) at 0° C. After stirring 1.5 h at 0°C. the mixture was concentrated in vacuo, washed with saturated aqueousNH₄Cl and extracted with CH₂Cl₂ (3×). The combined organics were washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo to affordthe above titled compound.

Example 3

[0082]({-[3-[(R)-3-(tert-Butyldimethylsilanyloxy)-5-oxocyclopent-1-enylsulfanyl]propylsulfanyl}aceticacid methyl ester (5).

[0083] The epoxide 3 prepared above was diluted with CH₂Cl₂ (30 mL),(3-mercaptopropylsulfanyl) acetic acid methyl ester 4 (1.93 g, 10.7mmol), prepared according to Chem. Pharm. Bull. 28 (2), 1980, 558-566,was added and the solution was cooled to 0° C. Basic alumina (11.9 g)was added and the reaction mixture was warmed to room temperature. Afterstirring for 18 h the mixture was filtered through celite andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 6:1 hex/EtOAc) to yield 3.6 g (80%) of theabove titled compound.

Example 4

[0084](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)oct-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)acetic acid methyl ester (7).

[0085] tert-Butyllithium (1.47 mL of a 1.7M solution in pentane, 2.5mmol) was added dropwise to a solution oftert-butyl[(S)-1-((E)-2-iodovinyl) hexyloxy]dimethylsilane 6 (462.5 mg,1.25 mmol) in Et₂O (6.0 mL) at −78° C. After stirring for 30 min lithium2-thienylcyanocuprate (6.0 mL of a 0.25M solution in THF, 1.5 mmol) wasadded and the reaction was stirred an additional 30 min at −78° C. Asolution of enone 5 (430 mg, 1.1 mmol) in Et₂O (1 mL) was added andstirring was continued for an additional 1 h. The reaction mixture wasthen quickly poured into saturated aqueous NH₄Cl cooled to 0° C. Themixture was extracted with EtOAc and the organic portion was washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The residuewas quickly purified by flash column chromatography (silica gel, 100%hexane followed by 8:1 hex/EtOAc) to afford 270 mg (39%) of the abovetitled compound.

Example 5

[0086]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (8).

[0087] Hydrogen fluoride-pyridine (220 μL) was added to a solution ofbis-TBDMS ether 7 (70 mg, 0.11 mmol) in CH₃CN (2.0 mL) at 0° C. Thereaction was warmed to room temperature, stirred 1 h, and recooled to 0°C. The reaction was quenched with saturated aqueous NaHCO₃ until gasevolution ceased. The mixture was extracted with CH₂Cl₂ (4×). Thecombined organics were washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 100% CH₂Cl₂ followed by 30:1 CH₂Cl₂:MeOH)provided 40 mg (90%) of the above titled compound.

Example 6

[0088]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (9).

[0089] Methyl ester 8 (50 mg, 0.124 mmol) was dissolved in CH₃CN (10 mL)and pH 7.2 phosphate buffer (3.0 mL) was added. The mixture was treatedwith PLE (400 μL, 1.34 mol/L) and stirred for 16 h at 23° C. Thereaction mixture was extracted with EtOAc (3×). The combined organicswere washed with brine, dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography(silica gel, 100% EtOAc) gave 5.3 mg (11%) of the above titled compound.

Example 7

[0090]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylulfanyl]propylsulfanyl}aceticacid isopropyl ester (10).

[0091] Isopropyl-p-tolyltriazene (200 μL) was added dropwise to asolution of carboxylic acid 9 (10.5 mg, 0.026 mmol) in acetone (5.0 mL)at 23° C. After stirring for 1 h the reaction was quenched with 1N HCland the solvent was removed in vacuo. The residue was extracted withCH₂Cl₂ (2×). The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 4:1 hex/EtOAc) gave 4.3 mg (38%) of theabove titled compound.

Example 8

[0092](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-5-(naphthyl)pent-1-enyl]-5oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (H).

[0093](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-5-(naphthyl)pent-1-enyl]-5oxocyclopentylsulfanyl]propylsulfanyl)aceticacid methyl ester (L).

[0094] The named compound is prepared by substitutingtert-butyl-[(E)-3-iodo-1-(2-naphthalen-2-yl-ethyl)allyloxy]dimethylsilane fortert-butyl[(S)-1-((E)-2-iodovinyl)hexyloxy]dimethylsilane in the methodof Example 4. FCC gives a higher Rf compound and a lower Rf compound,designated as H and L, respectively.

Example 9(H)

[0095]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0096] The named compound is prepared by repeating the method of Example5 with the named compound of Example 8 (H) rather then the namedcompound of Example 4.

Example 9 (L)

[0097]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0098] The named compound is prepared by repeating the method of Example5 with the named compound of Example 8 (L) rather then the namedcompound of Example 4.

Example 10 (H)

[0099]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0100] The named compound is prepared by repeating the method of Example6 with the named compound of Example 9 (H) rather than the namedcompound of Example 5.

Example 10 (L)

[0101]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0102] The named compound is prepared by repeating the method of Example6 with the named compound of Example 9 (L) rather than the namedcompound of Example 5.

Example 11

[0103]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-5-(naphthyl)pent-1-enyl)-5oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester.

[0104] The named compound is prepared by repeating the method of Example7 with the named compound of Example 10 rather than the named compoundof Example 6.

Example 12

[0105](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-5-(benzothienyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (H).

[0106](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-5-(benzothienyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (L).

[0107] The named compound is prepared by substituting[(E)-1-(2-Benzo[b)thiophen-2-yl-ethyl)-3-iodoallyloxy]-tert-butyldimethylsilanefor tert-butyl[(S)-1-((E)-2-iodovinyl)hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L, respectively.

Example 13(H)

[0108]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0109] The named compound is prepared by repeating the method of Example5 with the named compound of Example 12 (H) rather then the namedcompound of Example 4.

Example 13(L)

[0110]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0111] The named compound is prepared by repeating the method of Example5 with the named compound of Example 12 (H) rather then the namedcompound of Example 4.

Example 14(H)

[0112]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0113] The named compound is prepared by repeating the method of Example6 with the named compound of Example 13 (H) rather than the namedcompound of Example 5.

Example 14(L)

[0114]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0115] The named compound is prepared by repeating the method of Example6 with the named compound of Example 13 (L) rather than the namedcompound of Example 5.

Example 15

[0116]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzothienyl)pent-1enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester.

[0117] The named compound is prepared by repeating the method of Example7 with the named compound of Example 14 rather than the named compoundof Example 6.

Example 16

[0118](34(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-5-(benzofuranyl)pent-1-enyl]-5oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester.

[0119] The named compound is prepared by substituting[(E)-1-(2-Benzo[b]furan-yl-ethyl)-3-iodoallyloxy]-tert-butyldimethylsilanefor tert-butyl[(S)-1-((E)-2iodovinyl) hexyloxy]dimethylsilane in themethod of Example 4.

Example 17

[0120]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester.

[0121] The named compound is prepared by repeating the method of Example5 with the named compound of Example 16 rather then the named compoundof Example 4.

Example 18

[0122]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid.

[0123] The named compound is prepared by repeating the method of Example6 with the named compound of Example 17 rather than the named compoundof Example 5.

Example 19

[0124]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxy-5-(benzofuranyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester.

[0125] The named compound is prepared by repeating the method of Example7 with the named compound of Example 18 rather than the named compoundof Example 6.

Example 20

[0126](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(E)-3-(tert-butyldimethylsilanoxy)-4-naphthalen-2-yl-but-1-enyl]-5-oxocyclopentylsulfanyl]propylsulfanyl)aceticacid methyl ester (H).

[0127](3{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(E)-3-(tert-butyldimethylsilanoxy)-4-naphthalen-2-yl-but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (L).

[0128] The named compound is prepared by substitutingtert-butyl-((E)-3-iodo-1-naphthalen-2-yl-methylallyloxy)dimethylsilanefor tert-butyl[(S)-1-((E)-2-iodovinyl) hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L, respectively.

Example 21 (H)

[0129]3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0130] The named compound is prepared by repeating the method of Example5 with the named compound of Example 20 (H) rather then the namedcompound of Example 4.

Example 21(L)

[0131]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0132] The named compound is prepared by repeating the method of Example5 with e named compound of Example 20 (H) rather then the named compoundof ample 4.

Example 22(H)

[0133]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0134] The named compound is prepared by repeating the method of Example6 with the named compound of Example 21 (H) rather than the namedcompound of Example 5.

Example 22(L)

[0135]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-4-naphthalen-2-yl-but-1-enyl)-5oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0136] The named compound is prepared by repeating the method of Example6 with the named compound of Example 21 (H) rather than the namedcompound of Example 5.

Example 23

[0137]{3-[(1R,2S,3R)-2-[(E)-4-Benzo[b]thiophen-3-yl-3-(tert-butyldimethylsilanyloxy)but-1-enyl]-3-(tert-butyldimethylsilanyloxy)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0138]{3-[(1R,2S,3R)-2-[(E)-4-Benzo[b]thiophen-3-yl-3-(tert-butyldimethylsilanyloxy)but-1-enyl]-3-(tert-butyldimethylsilanyloxy)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0139] The named compound is prepared by substituting((E)-1-Benzo[b]thiophen-3-ylmethyl-3-iodo-allyloxy)-tert-butyldimethylsilanefor tert-butyl[(S)-1-((E)-2-iodovinyl)hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L respectively.

Example 24(H)

[0140]{3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0141] The named compound is prepared by repeating the method of Example5 with the named compound of Example 23 (H) rather then the namedcompound of Example 4.

Example 24(L)

[0142]{3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0143] The named compound is prepared by repeating the method of Example5 with the named compound of Example 23 (H) rather then the namedcompound of Example 4.

Example 25(H){3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0144] The named compound is prepared by repeating the method of Example6 with the named compound of Example 24 (H) rather than the namedcompound of Example 5.

Example 25(L)

[0145]{3-[(1R,2S,3R)-2-((E)-4-Benzo[b]thiophen-3-yl-3-hydroxybut-1-enyl)-3-hydroxy-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0146] The named compound is prepared by repeating the method of Example6 with the named compound of Example 24 (H) rather than the namedcompound of Example 5.

Example 26

[0147](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-3-(methyl)-5-(naphthyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (H).

[0148](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-3-(methyl)-5-(naphthyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (L).

[0149] The named compound is prepared by substitutingtert-Butyl-[(E)-3-iodo-1-methyl-1-(2-naphthalen-2-yl-ethyl)allyloxy]dimethylsilanefor tert-butyl[(S)-1-((E)₂-iodovinyl)hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L, respectively.

Example 27(H)

[0150]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0151] The named compound is prepared by repeating the method of Example5 with the named compound of Example 26 (H) rather then the namedcompound of Example 4.

Example 27(L)

[0152]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0153] The named compound is prepared by repeating the method of Example5 with the named compound of Example 26 (H) rather then the namedcompound of Example 4.

Example 28(H)

[0154]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl)aceticacid (H).

[0155] The named compound is prepared by repeating the method of Example6 with the named compound of Example 27 (H) rather than the namedcompound of Example 5. Example 28(L

[0156]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(naphthyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0157] The named compound is prepared by repeating the method of Example6 with the named compound of Example 27(L) rather than the namedcompound of Example 5.

Example 29

[0158](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(E)-3-(tert-butyldimethylsilanoxy)-3-methyl-4-naphthalen-2-yl-but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (H).

[0159](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(E)-3-(tert-butyldimethylsilanoxy)-3-methyl-4-naphthalen-2-yl-but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (L).

[0160] The named compound is prepared by substitutingtert-butyl-[(E)-3-iodo-1-ethyl-1-(2-naphthalen-2-yl-methyl)allyloxy]dimethylsilanefor tert-butyl[(S)-1-(E)-2-iodovinyl) hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L, respectively.

Example 30(H)

[0161]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0162] The named compound is prepared by repeating the method of Example5 with the named compound of Example 29 (H) rather then the namedcompound of Example 4.

Example 30(L)

[0163]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0164] The named compound is prepared by repeating the method of Example5 with the named compound of Example 29 (L) rather then the namedcompound of Example 4.

Example 31(H)

[0165]3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0166] The named compound is prepared by repeating the method of Example6 with the named compound of Example 30 (H) rather than the namedcompound of Example 5.

Example 31(L)

[0167]{3-[(1R,2S,3R)-3-Hydroxy-2-((E)-3-hydroxy-3-methyl-4-naphthalen-2-yl-but-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0168] The named compound is prepared by repeating the method of Example6 with the named compound of Example 30 (L) rather than the namedcompound of Example 5.

Example 32

[0169](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-3-(methyl)-5-(benzylthienyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (H).

[0170](3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)-3-(methyl)-5-(benzothienyl)pent-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (L).

[0171] The named compound is prepared by[(E)-1-(2-Benzo[b]thiophen-2-ylethyl)-3-iodo-1-methylallyloxy]-tert-butyldimethylsilanefor tert-butyl[(S)-1-((E)-2-iodovinyl) hexyloxy]dimethylsilane in themethod of Example 4. FCC gives a higher Rf compound and a lower Rfcompound, designated as H and L, respectively.

Example 33(H)

[0172]{3-[(1R,2S,3-R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (H).

[0173] The named compound is prepared by repeating the method of Example5 with the named compound of Example 32 (H) rather then the namedcompound of Example 4.

Example 33(L)

[0174]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester (L).

[0175] The named compound is prepared by repeating the method of Example5 with the named compound of Example 32 (L) rather then the namedcompound of Example 4.

Example 34(H)

[0176]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (H).

[0177] The named compound is prepared by repeating the method of Example6 with the named compound of Example 33 (H) rather than the namedcompound of Example 5.

Example 34(L)

[0178]{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-(hydroxy)-3-(methyl)-5-(benzothienyl)pent-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid (L).

[0179] The named compound is prepared by repeating the method of Example6 with the named compound of Example 33L rather than the named compoundof Example 5.

[0180] The effects of the compounds of this invention on intraocularpressure may be measured as follows. The compounds are prepared at thedesired concentrations in a vehicle comprising 0.1% polysorbate 80 and10 mM TRIS base. Dogs are treated by administering 25 μl to the ocularsurface, the contralateral eye receives vehicle as a control.Intraocular pressure is measured by applanation pneumatonometry. Dogintraocular pressure is measured immediately before drug administrationand at 6 hours thereafter.

[0181] The compounds of Examples 9H, 9L, 10H, 10L, 13H, 13L, 14H, 14L,21H, 21L, 22H, 22L, 24H, 25H, 25L, 27H, 27L, 28H, 28L, 30H, 30L, 31H,31L, 33H, 33L, 34H and 34L are useful in lowering elevated intraocularpressure in mammals, e.g. humans.

[0182] The compounds of the Examples are subject to in vitro testing asdescribed below. The results are reported in the table. Ex- ample No.hEP₄ 33H

200 33L

300 34H

32 34L

68 13H

91 13L

93 14H

27 14L

13 9H

40 9L

40 10H

450 10L

19.5 27H

500 27L

3400 28H

1700 28L

1500 21H

100 21L

13 22H

32 22L

6.2 30H

3100 30L

3200 31H

300 31L

900 24H

200 24L

30 25H

69 25L

5

[0183] Human Recombinant EP₄ Receptor: Stable Transfectants.

[0184] Plasmids encoding the human EP₄ receptor were prepared by cloningthe respective coding sequences into the eukaryotic expression vectorpCEP4 (Invitrogen). The pCEP4 vector contains an Epstein Barr virus(EBV) origin of replication, which permits episomal replication inprimate cell lines expressing EBV nuclear antigen (EBNA-1). It alsocontains a hygromycin resistance gene that is used for eukaryoticselection. The cells employed for stable transfection were humanembryonic kidney cells (HEK-293) that were transfected with and expressthe EBNA-1 protein. These HEK-293-EBNA cells (Invitrogen) were grown inmedium containing Geneticin (G418) to maintain expression of the EBNA-1protein. HEK-293 cells were grown in DMEM with 10% fetal bovine serum(FBS), 250 μg ml⁻¹ G418 (Life Technologies) and 200 μg ml⁻¹ gentamicinor penicillin/streptomycin. Selection of stable transfectants wasachieved with 200R⁹ ml⁻¹ hygromycin, the optimal concentration beingdetermined by previous hygromycin kill curve studies.

[0185] For transfection, the cells were grown to 50-60% confluency on 10cm plates. The plasmid pCEP4 incorporating cDNA inserts for therespective human prostanoid receptor (20 μg) was added to 500 μl of 250mM CaCl₂. HEPES buffered saline×2 (2×HBS, 280 mM NaCl, 20 mM HEPES acid,1.5 mM Na₂ HPO₄, pH 7.05-7.12) was then added dropwise to a total of 500μl, with continuous vortexing at room temperature. After 30 min, 9 mlDMEM were added to the mixture. The DNA/DMEM/calcium phosphate mixturewas then added to the cells, which had been previously rinsed with 10 mlPBS. The cells were then incubated for 5 hr at 37° C. in humidified 95%air/5% CO₂. The calcium phosphate solution was then removed and thecells were treated with 10% glycerol in DMEM for 2 min. The glycerolsolution was then replaced by DMEM with 10% FBS. The cells wereincubated overnight and the medium was replaced by DMEM/10% FBScontaining 250 μg ml⁻¹ G418 and penicillin/streptomycin. The followingday hygromycin B was added to a final concentration of 200 μg ml⁻.

[0186] Ten days after transfection, hygromycin B resistant clones wereindividually selected and transferred to a separate well on a 24 wellplate. At confluence each clone was transferred to one well of a 6 wellplate, and then expanded in a 10 cm dish. Cells were maintained undercontinuous hygromycin selection until use.

[0187] The foregoing description details specific methods andcompositions that can be employed to practice the present invention, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. Similarly,different pharmaceutical compositions may be prepared and used withsubstantially the same result. For example, the EP4 agonists disclosedand claimed U.S. Pat. No. 6,410,591 B1, which is hereby incorporated byreference may be used in the method of the present invention. Inaddition, GR 50209×, a receptor selective EP₄-receptor agonist, may alsobe used in the method of the present invention. (GR 50209×has thefollowing structure:

[0188] Thus, however detailed the foregoing may appear in text, itshould not be construed as limiting the overall scope hereof; rather,the ambit of the present invention is to be governed only by the lawfulconstruction of the appended claims.

1. A method of treating ocular hypertension or glaucoma which comprisesadministering to an animal having ocular hypertension or glaucoma atherapeutically effective amount of a compound which is an EP₄ agonist.2. The method of claim 1 wherein said compound is represented by thegeneral formula I;

wherein hatched lines represent the a configuration, a trianglerepresents the β configuration, a wavy line represents either the aconfiguration or the β configuration and a dotted line represents thepresence or absence of a double bond; A and B are independently selectedfrom the group consisting of O, S and CH₂, provided that at least one ofA or B is S; D represents a covalent bond or CH₂, O, S or NH; X is CO₂R,CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Y is O, OH, OCOR², halogen or cyano; Z is CH₂ or a covalent bond; R is Hor R²; R¹ is H, R², phenyl, or COR²; R² is C₁-C₅ lower alkyl or alkenyl;R₃ is benzothienyl, benzofuranyl, naphthyl, or substituted derivativesthereof, wherein the substituents maybe selected from the groupconsisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, NR², CO₂R and OR andR⁴ is hydrogen or C₁-C₅ lower alkyl.
 3. The method according to claim 2wherein said compound is represented by the general formula II;


4. The method according to claim 3 wherein said compound is representedby the general formula III;


5. The method of claim 2 wherein Z represents a covalent bond.
 6. Themethod of claim 2 wherein D represents a covalent bond or is CH₂.
 7. Themethod of claim 2 wherein X is CO₂ R.
 8. The method of claim 7 wherein Ris selected from the group consisting of H, methyl, i-propyl, andn-propenyl.
 9. The method of claim 2 wherein R is H, or n-propenyl. 10.The method of claim 2 wherein R¹ is H.
 11. The method of claim 2 whereinD is CH₂.
 12. The method of claim 11 wherein R³ is benzo[b]thienyl,3-chlorobenzo[b]thienyl or naphthyl.
 13. An ophthalmic solutioncomprising a therapeutically effective amount of a compound which is EP₄agonist.
 14. A pharmaceutical product, comprising a container adapted todispense the contents of said container in metered form; and anophthalmic solution according to claim 13 in said container.
 15. Themethod of claim 1 wherein said compound is GR 50209X.